The present invention relates to a novel series of anthranilic acid-derived amides (I) having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel and chloride channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews [Rudy, B. Neuroscience 1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12, 569-591; Gopalakrishnan, M. et al., Drug Development Research 1993, 28, 95-127; Primeau, J. et al. Current Pharmaceutical Design 1995, 1, 391-406; Edwards, G. et al. Exp. Opin. Invest. Drugs 1996, 5 (11), 1453-1464]. Therapeutic potential for potassium channel modulators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
Research interests in the modulation of chloride channels are growing at a fast pace [Strange, K. et al. Kidney International 1995, 48, 994-1003; Franciolini, F. et al. Biochimica et Biophysica Acta 1990, 247]. Various disease states potentially amenable to chloride channel modulation include bronchial asthma, cardiac arrhythmias, cystic fibrosis, and kidney disease.
Harita et al. disclose a process for the manufacturing of a class of meta-substituted aromatic amide carboxylic acid derivatives in Japanese Patent Application No. 49-102692, and also builds on a method for manufacturing aromatic cinammic acid derivatives in Japanese Patent Application No. 49-42465. Several patents and patent applications focus particularly on agents possessing claims of anti-allergic/anti-asthmatic/anti-histaminic activity: Sato et al. report a group of anthranilic acid derivatives (highlighting Tranilast.RTM. as an anti-allergic-agent) in Japanese Patent Application No. 57-179976; related to these anthranilates is a claim by Aoyanagi et. al. in Japanese Patent Application No. 58-79436 which discloses a method for manufacturing anthranilic acid derivatives; also related is Hungarian Patent HU 200 996 B which emphasizes the production of several Tranilast.RTM. analogs; and Yukihiko, in Japanese Patent No. J6 0019-754-A, has also indicated a method for the preparation of anthranilic acid derivatives where the styrenyl portion is strictly limited to alkoxy, hydroxy or acyloxy.
In addition, Japanese Patent No. J0 2218-654-A by Tsumoro et al. which reveals a class of amino-benzoic acid derivatives which are useful as reverse transcriptase inhibitors. Also by Tsumoro et al., Patent No. J6 0097-946-A discloses a series of substituted carboxamide derivatives which exhibit activity as leucotriene antagonists and phospholipase inhibitors.